JPH0463874B2 - - Google Patents
Info
- Publication number
- JPH0463874B2 JPH0463874B2 JP59113043A JP11304384A JPH0463874B2 JP H0463874 B2 JPH0463874 B2 JP H0463874B2 JP 59113043 A JP59113043 A JP 59113043A JP 11304384 A JP11304384 A JP 11304384A JP H0463874 B2 JPH0463874 B2 JP H0463874B2
- Authority
- JP
- Japan
- Prior art keywords
- hotimicin
- streptomyces
- acid
- compound
- culture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 claims description 27
- 241000187747 Streptomyces Species 0.000 claims description 14
- 241000894006 Bacteria Species 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 241001147843 Streptomyces tenjimariensis Species 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- -1 formimidoylglycyl group Chemical group 0.000 claims description 3
- 239000001963 growth medium Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 29
- 239000000243 solution Substances 0.000 description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 20
- 239000002609 medium Substances 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000126 substance Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229920001817 Agar Polymers 0.000 description 11
- 239000008272 agar Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 230000001580 bacterial effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 244000063299 Bacillus subtilis Species 0.000 description 5
- 235000014469 Bacillus subtilis Nutrition 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229920001429 chelating resin Polymers 0.000 description 5
- 229930190043 istamycin Natural products 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 239000000049 pigment Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- DPEYHNFHDIXMNV-UHFFFAOYSA-N (9-amino-3-bicyclo[3.3.1]nonanyl)-(4-benzyl-5-methyl-1,4-diazepan-1-yl)methanone dihydrochloride Chemical compound Cl.Cl.CC1CCN(CCN1Cc1ccccc1)C(=O)C1CC2CCCC(C1)C2N DPEYHNFHDIXMNV-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VFBPKQSATYZKRX-WKEGKRRDSA-N Formimidoyl-fortimicin A Chemical compound O[C@@H]1[C@H](N(C)C(=O)CN=CN)[C@@H](OC)[C@@H](O)[C@H](N)[C@H]1O[C@@H]1[C@H](N)CC[C@@H]([C@H](C)N)O1 VFBPKQSATYZKRX-WKEGKRRDSA-N 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 241000209140 Triticum Species 0.000 description 3
- 235000021307 Triticum Nutrition 0.000 description 3
- 239000003957 anion exchange resin Substances 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003729 cation exchange resin Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003795 desorption Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 239000001888 Peptone Substances 0.000 description 2
- 108010080698 Peptones Proteins 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 238000012136 culture method Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
- 235000019319 peptone Nutrition 0.000 description 2
- 239000002952 polymeric resin Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011218 seed culture Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 description 2
- ROBLTDOHDSGGDT-UHFFFAOYSA-M sodium;pentane-1-sulfonate Chemical compound [Na+].CCCCCS([O-])(=O)=O ROBLTDOHDSGGDT-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229920003002 synthetic resin Polymers 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- UQZSVIGPZAULMV-DKWTVANSSA-N (2s)-2,4-diamino-4-oxobutanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.OC(=O)[C@@H](N)CC(N)=O UQZSVIGPZAULMV-DKWTVANSSA-N 0.000 description 1
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- GUTLYIVDDKVIGB-OUBTZVSYSA-N Cobalt-60 Chemical compound [60Co] GUTLYIVDDKVIGB-OUBTZVSYSA-N 0.000 description 1
- RFSUNEUAIZKAJO-VRPWFDPXSA-N D-Fructose Natural products OC[C@H]1OC(O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-VRPWFDPXSA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- SPTSIOTYTJZTOG-UHFFFAOYSA-N acetic acid;octadecanoic acid Chemical compound CC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O SPTSIOTYTJZTOG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000999 acridine dye Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- AIUDWMLXCFRVDR-UHFFFAOYSA-N dimethyl 2-(3-ethyl-3-methylpentyl)propanedioate Chemical class CCC(C)(CC)CCC(C(=O)OC)C(=O)OC AIUDWMLXCFRVDR-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003495 flagella Anatomy 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 235000021312 gluten Nutrition 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000013028 medium composition Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000006877 oatmeal agar Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001477 organic nitrogen group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940066779 peptones Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000009958 sewing Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 229940045870 sodium palmitate Drugs 0.000 description 1
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- QWSZRRAAFHGKCH-UHFFFAOYSA-M sodium;hexane-1-sulfonate Chemical compound [Na+].CCCCCCS([O-])(=O)=O QWSZRRAAFHGKCH-UHFFFAOYSA-M 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
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ïŒ 30.85 6.90 11.99
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瀺ãéãã§ããã
ç¹åŸŽçã·ã°ãã«ïŒ1.35ppmïŒïœã3HãïŒ6.5
HzïŒâŠ6â²ââã¡ãã«ã1.6ppmïŒm1HïŒâŠ
4â²âã¡ãã¬ã³ã2.03ppmã2.15ppmïŒm3HïŒ
âŠ3â²ïŒ4â²âã¡ãã¬ã³ã3.15ppmïŒïœã3HïŒâŠ
ïŒââã¡ãã«ã3.41ppmïŒïœã1HJ6â²ãCH3
ïŒ6.5HzïŒâŠ6â²âã¡ãã³ã3.51ppmïŒïœã3HïŒ
ïŒâïŒâã¡ãã«ã3.60ppmïŒïœã1HïŒâŠ2â²â
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3.93ppmïŒïœã1H.J1;2ïŒ3.6HzïŒJ1ïŒ6ïŒ3.6
HzïŒâŠïŒâã¡ãã³ã4.06ppmïŒïœãïœã1Hã
J3ïŒ2ïŒ3.3HzïŒJ3;4ïŒ11HzïŒïŒâã¡ãã³ã
4.23ppmïŒïœïŒ1HïŒâŠïŒâã¡ãã³ã3.38ppm
ïŒïœã1HãïŒ17.5HzïŒããã³4.47ppmïŒïœã
1HãïŒ17.5HzïŒ2â³âã¡ãã¬ã³4.42ppm
ïŒ1HïŒâŠïŒã¡ãã¬ã³ã4.66ppmïŒïœãïœã
1HïŒâŠïŒâã¡ãã¬ã³ã4.7ppmïŒïœã1HïŒâŠ
ïŒâã¡ãã³ã5.46ppmïŒïœã1HãJ1â²,2â²ïŒ3.2
HzïŒâŠ1â²âã¢ãã¡ãªãã¯ãããã³ã7.98ppm
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The present invention relates to 1-epidactymicin, a novel dactymicin derivative having antibacterial activity, or a salt thereof. Furthermore, the present invention provides the production of 1-epidactymicin by microbially converting the chemical structure of hotimicin B using a strain of the genus Streptomyces that does not have the ability to produce hotimicin B but has the ability to convert hotimicin B into a dactymicin derivative. It concerns the manufacturing method. 1-Epidactymicin or its acid addition salt provided by the present invention exhibits excellent antibacterial activity and is extremely useful as an antibacterial agent. The following formula Hotimicin B, represented by
of Antibiotics, Vol. 30, pp. 533-570 (197)), but its antibacterial activity is not necessarily satisfactory. During research to produce an antibiotic superior to Hotimicin B, the present inventors found that Hotimicin B was converted to a dactymicin derivative represented by the following formula [] when treated with a certain type of microorganism. did. Dactymicin is a compound described in JP-A-55-64597 under the name of substance SF-2052. Therefore, according to the first invention, the following three-dimensional structural formula 1-epidactymicin or an acid addition salt thereof is provided. 1-epidactymicin corresponds to 1-epi-2''-formimidoylhotymicin A. The compound of the present invention of formula []
It has a chemical structure corresponding to that in which the amino group at position is epitomized and the methylamino group at position 4 is formimidoyl glycylated. The compound of this formula [] (lyophilized product) exhibits the following physical and chemical properties. (1) Basic sulfate of this substance: white powder (2) Solubility: extremely soluble in water, methanol,
Ethanol, acetone, chloroform, benzene, ethyl acetate, butyl acetate, ether, n-
It is insoluble in organic solvents such as hexane. (3) Elemental analysis value (C 18 H 36 N 6 O 6ã»2H 2 SO 4ã»4H 2 O
): C H N Theoretical value (%) 30.85 6.90 11.99 Experimental value (%) 30.78 7.01 12.00 (4) Melting point: Gradual thermal decomposition (accompanied by browning, foaming, and melting) above 205°C (5) Optical rotation: [α] 21 D +92° (c=0.15%; H 2 O) (6) Ultraviolet absorption spectrum: Terminal absorption (7) Infrared absorption spectrum (KBr tablet): As shown in FIG. Maximum absorption (cm -1 ): 3400, 2940, 2040, 1715,
1630, 1500, 1400, 1360, 1325, 1260,
1110, 1040 (8) Nuclear magnetic resonance spectrum (in heavy water): As shown in Figure 2. Characteristic signal: 1.35ppm (d, 3H, J = 6.5
Hz)...6'-C-methyl, 1.6ppm (m1H)...
4â²-methylene, 2.03ppm to 2.15ppm (m3H)
...3',4'-methylene, 3.15ppm (s, 3H)...
4-N-Methyl, 3.41ppm (m, 1HJ6 ', CH3
= 6.5Hz)...6'-methine, 3.51ppm (s, 3H)
3-0-methyl, 3.60ppm (m, 1H)...2'-
Methine-,. 88ppm (1H)âŠ5â²-methine,
3.93ppm (t, 1H.J 1 ; 2 = 3.6Hz, J 1 ; 6 = 3.6
Hz)...1-methine, 4.06ppm (d, d, 1H,
J 3 ; 2 = 3.3Hz, J 3 ; 4 = 11Hz) 3-methine,
4.23ppm (t, 1H)...6-methine, 3.38ppm
(d, 1H, J=17.5Hz) and 4.47ppm (d,
1H, J=17.5Hz) 2â³-methylene 4.42ppm
(1H)...5 methylene, 4.66ppm (d, d,
1H)...4-methylene, 4.7ppm (t, 1H)...
2-methine, 5.46 ppm (d, 1H, J 1 â² , 2 â² = 3.2
Hz)...1â²-anomeric proton, 7.98ppm
(s, 1H)...3 (formimidoyl) proton (9) Molecular ion peak in mass spectrum (SIMS): 433 (M+1) (10) Retention time by high performance liquid chromatography: As shown in Table 1 be.
ãè¡šããtableã
ãè¡šã
(11) èå±€ã¯ãããã°ã©ãã€ãŒã«ããRfå€ïŒç¬¬ïŒ
è¡šã«ç€ºãéãã§ããã[Table] (11) Rf value by thin layer chromatography: 2nd
As shown in the table.
ãè¡šããtableã
ãè¡šã
æ¬çºæã«ããåŒããã®ååç©ã®æèã¹ãã¯ã
ã«ãããŒããã·ã³ïŒ¢ïŒFMâãšç¥èšããïŒãããŒ
ããã·ã³ïŒ¡ïŒFMâãšç¥èšããïŒããã¯ããã·ã³
ïŒDACãšç¥èšããïŒãšå¯Ÿæ¯ããŠæ¬¡ã®ç¬¬ïŒè¡šã«ç€º
ãã[Table] The antibacterial spectrum of the compound of formula [] according to the present invention is compared with Hotimicin B (abbreviated as FM-B), Hotimicin A (abbreviated as FM-A), and Dactimicin (abbreviated as DAC) as follows. It is shown in Table 3.
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ãã·ã³ã§ãããšåå®ãããã[Table] As is clear from the above table, the compound of the present invention of formula [] exhibits a wide range of strong antibacterial activity against various Gram-positive and Gram-negative bacteria, and especially compared to the starting material Hotimicin B, The antibacterial activity is enhanced by a factor of two to several tens of times, and it has a stronger antibacterial activity that is comparable to Hotimicin A and Dactimicin. Examples of acid addition salts of compounds of the invention include pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or organic acids such as acetic acid,
There are salts with propionic acid, citric acid, metal sulfonic acid, etc. According to the second aspect of the present invention, Hotimicin B includes one of Hotimicin B that belongs to the genus Streptomyces.
A method for producing 1-epidactymicin of the above formula [] or an acid addition salt thereof, which comprises using a bacterium capable of epitomizing the amino group at the position and introducing a formimidoylglycyl group into the methylamino group at the 4-position. is provided. According to the method of the present invention, the compound [] is produced by contacting Hotimicin B with a bacterial bead belonging to the genus Streptomyces and having the above-mentioned conversion ability or a mutant strain thereof. There are no particular limitations on the strain used in the method of the present invention, as long as it can epiform the amide group at position 1 of the fotamin moiety and formimidoylglysylate the methylamino group at position 4. Examples of fungal beads that can be used in the method of the present invention include:
Streptomyces tenzimariensis, known as istamycin-producing bacterium
tenjimariensis) SS-939 strain (FERM-P4932)
(Refer to Japanese Patent Application Laid-Open No. 55-145697), and Streptomyces tenzimariensis SS1507
can be given. This strain SS-1507 has been deposited with the National Institute of Microbiology, Agency of Industrial Science and Technology, and its accession number is FERM-P. Mutant strains can be obtained from istamycin-producing strains belonging to the genus Streptomyces by using, for example, ultraviolet irradiation, cobalt-60 irradiation, X-ray irradiation, or mutagenic agents such as nitroso compounds, acridine dye compounds, and nucleobase analogues. There are things that can be obtained through artificial mutation. Suitable mutant strains for use in this method include those that do not have the ability to produce istamycin or have an extremely reduced ability to produce istamycin.
Moreover, it has the property of being capable of epitomizing the amino group at the 1-position of Hotimicin B and converting the methylamino group at the 4-position to formimidoylglucylation. A representative example of these mutant strains that can be used in the method of the present invention is Streptomyces tenjimariensis SS-1507U-, which the present inventors derived from Streptomyces tenjimariensis SS-1507. 41
can be given. This strain has been deposited with the Institute of Microbial Technology, Agency of Industrial Science and Technology, and its accession number is FERM-P7625. These Streptomyces tenjimariensis SS-1507 and Streptomyces tenjimariensis SS-1507U-41
The mycological properties of both are exactly the same and are as shown below. (A) Morphology Streptomyces tenzimariensis growing well on agar medium
strain SS-1507 and Streptomyces tenjimariensis SS-1507U-
Strain 41 has simple branching and extends straight or slightly curved aerial hyphae from well-elongated basal hyphae.
When mature, it forms a chain of 10 to 50 long cylindrical (1 micron wide, 4 to 5 micron long) spores at the tip. No spirals or axle branches are shown. Under an electron microscope, the spore surface is smooth and does not have any spine-like or hair-like structures. It is a typical Streptomyces without flagella or sporangia. (B) Characteristics on various media Seuucrose/nitrate agar medium (cultured at 27°C); white aerial hyphae appear on weak colorless growth, gradually turning blue-green to gray (17ec,
aqua blue, according to the Color Harmony Manual; the same applies hereafter). It does not produce significant diffusible pigments in the medium. Glycerin-asparagine agar medium (27â
culture); however, aerial mycelia are difficult to attach to. It is almost the same as starch agar medium (cultured at 27â); however, aerial mycelium grows on it, and the starch around the bacterial growth becomes transparent. The findings are almost the same as those on tyrosine agar medium (cultured at 27°C); melanin-like pigments are produced. Nutrient agar medium (cultured at 27°C): White aerial mycelium grows on colorless growth, and the medium becomes brownish. Yeast/malt agar medium (cultured at 27°C): White aerial mycelium grows on colorless growth, gradually turning blue-greenish gray (19bc aqua gray). The medium appears brownish in color. Oatmeal agar medium (cultured at 27â); colorless growth with white to blue-gray color (17ec, aqua
Aerial mycelia with a blue color are attached. (C) Physiological properties Can grow at 20-41â. Hydrolyze the starch on starch agar. Hardly any coagulation or peptonization of skim milk is observed. Melanin-like pigments are produced on tyrosine agar and peptone yeast iron agar. (D) Assimilation of carbon sources (on Prittham-Gotzlieb agar medium) Only glucose and inositol are assimilated, and arabinose, D-xylose, sucrose, rhamnose, raffinose, and D-mannite are not assimilated. Assimilation of D-fructose is questionable. The above properties have already been reported by the present inventors, and istamycin-producing bacterial beads, Streptomyces tenzimariensis SS-939 strain (Japanese Unexamined Patent Application Publication No. 1989-1982)
145697), the ability to form aerial mycelia, the production of melanin-like pigments, the color tone of aerial mycelium, and the assimilation of carbon sources are exactly the same, but Streptomyces tenzimariensis SS-1507U-41 strain It is unique in that it has almost no ability to produce mycin, and is convenient for use in the method of the present invention. To carry out the method of the present invention, in order to convert Ho Chi Minh B into the compound [], Ho Chi Minh B
Generally, the above-mentioned strains of Streptomyces tenzimariensis, which can be used in the method of the present invention, may be cultured in a medium containing . That is, the above-mentioned method is made to work by allowing Hotimicin B to exist in the culture solution in which the bacteria are being cultured. In culturing bacteria in the method of the present invention, conventional culture methods for producing antibiotics are used. Various nutrient sources can be used for culture. Glucose as a carbon source,
Starch dextrin, sucrose, molasses, etc. can be used alone or in combination, and depending on the assimilation ability of the bacteria, hydrocarbons, alcohols, organic acids, animal oils, vegetable oils, etc. can also be used. Inorganic nitrogen sources and organic nitrogen sources include ammonium chloride, ammonium nitrate, sodium nitrate, soybean flour, defatted soybean flour, cottonseed meal, gluten meal, cornmeal, wheat germ, peptones, meat extract, yeast extract, and drying. Yeast, corn steep liquor, etc. may be used alone or in combination. In addition, amino acids, nucleic acids, vitamins, sodium chloride,
Calcium carbonate, phosphate, magnesium nitrate,
Inorganic salts such as cobalt chloride can also be added. As a culture method, a liquid culture method, particularly a method using a deep stirring method, is suitable. Culture temperature is 20â~41â
â, preferably 25â to 32â, and the pH is preferably around neutral. It goes without saying that culture conditions such as medium composition, liquid properties of the medium, amount of additives, temperature, number of stirrings, amount of aeration, etc. are appropriately selected depending on the bacterial beads used. In order to obtain the compound [], the raw material Hotimicin B may be added at the start of the culture or after the bacteria have grown, but it is preferable to add it within about 96 hours after the start of the culture. The amount of raw materials to be added is approximately 0.1 to 10 g per 1 g of the medium, which may be added all at once, or may be added in portions. Further, Hotimicin B to be added may be in the form of a free base, but may also be in the form of a salt, such as a sulfate or a hydrochloride. The action time of the bacteria and hotimicin B is selected so that the compound [] is accumulated in the largest amount after the addition of the raw materials.
This is for example Bacillus subtilis.
subtilis) PCI219 as a test strain, the amount of the compound [ ] in the culture solution can be monitored using the paper desk method, but it usually takes 3 to 9 days. The method for collecting the compound [], including its isolation and purification from the culture solution, is the method normally used for collecting aminoglycoside antibiotics. Namely, adsorption and desorption methods using cation and anion exchange resins, adsorption and desorption methods using porous polymer resins using counter ions, adsorption and desorption methods using activated carbon,
Methods such as silica gel column chromatography can be used in appropriate combination. Specifically, in order to collect the compound [] from the culture solution, for example, the pH of the culture solution is adjusted to 2 to 3, the bacterial cells are removed by sieving, and the PH is adjusted to 5 to 6 again. Carboxylic acid groups, sulfonic acid groups suitable for adsorption and elution of substances with this chemical structure,
Amberlite IRC-50 (trade name) [Na + ] as a cation exchange resin with etc., Dowex
Adsorb with 50W (trade name) [Na + ], etc., and elute with 0.5N sulfuric acid to obtain a crude solution containing compound [T].
In order to further purify this substance, we used sodium 1-pentanesulfonate, sodium 1-hexanesulfonate, sodium 1-heptanesulfonate, sodium 1-octanesulfonate, sodium 1-dodecanesulfonate, and sodium 1-dodecanesulfonate as counterion agents. Select an appropriate one from sodium dodecylsulfonate, sodium paratoluenesulfonate, etc., add it and dissolve it, and gradually add about 0.5 to 1N of sodium hydroxide.
After adjusting the pH to 5.0, porous polymer resins Amberlite XAD-2 (trade name), Amberlite XAD-4 (trade name), Diaion HP-20
(product name), Diaion CPH-20P (product name), etc. After adsorbing these and washing the resin thoroughly with water, the metal concentration of the elution solvent was adjusted to
The concentration is gradually increased from 0 stepwise or by concentration gradient method until each substance is eluted. The fractions of each substance eluted in this way were collected and neutralized to pH 6.0 with approximately 0.5N sodium hydroxide, and then mixed with cation exchange resin Amberlite IRC-50 (trade name) [Na + ]. ,
Adsorb to CG-50 (trade name) [Na + ], wash well with water, and elute with 0.5N sulfuric acid. This measures the separation from the counter ion agent used.
This eluate contains a large amount of sodium sulfate in addition to the substance of formula [], so it is adsorbed on activated carbon and washed with water to wash away the sodium sulfate, and then eluted with 80% methanol containing 0.05N sulfuric acid. Since the eluate is sulfuric acid, after concentrating it to an appropriate concentration, it is mixed with Amberlite IRA-45, an anion exchange resin.
(Product name) After neutralizing with [OH - ] and separating, anion exchange resin IRA-400 (Product name)
The target substance of the formula [] is obtained by passing [SO 4 -- ] through it, concentrating the aqueous solution that has passed through it, and then freeze-drying it. This basic compound [] readily forms non-toxic acid addition salts when reacted with inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid stearic acid, tartaric acid, maleic acid, etc. in a conventional manner. . Next, the present invention will be further explained with reference to Examples. Example 1 Streptomyces grown well by culturing on soluble starch inorganic salt (ISP No. 4) agar medium for 2 weeks.
Streptomyces
tenjimariensis) SS1507Uâ41 (FERMâP7625)
was inoculated into a sterilized 500 ml flask with 100 ml of a liquid medium (PH 7.0) containing 6.0% cornmeal, 2.0% wheat germ, 0.05% magnesium sulfate, and 0.6% calcium carbonate, and incubated at 27°C for 48 hours. A seed culture solution was obtained by shaking culture for ~72 hours. Separately, prepare 100 ml of main culture medium in a 500 ml flask, and inoculate it with 1 ml of the above seed culture medium. The composition of this medium is 6.5% wheat germ, 0.5% sodium palmitate, 0.05% magnesium sulfate, 0.6% calcium carbonate,
It contains 3.5% soybean oil (PH7.0) and is used after being sterilized at 120°C for 17 minutes. Hochi Sewing Machine B 72 hours after inoculation
(base) was added at 300 mcg per ml of medium. After adding this raw material, shaking culture was performed at 27°C for 168 hours.
By the way, at that time Bacillus subtilis PCI
When the antibacterial activity of the culture solution was measured using the -219 strain by the paper dice method, an inhibition circle of 21.9 mm in diameter was obtained. After adjusting the pH of 22 flasks of the obtained culture solution to 2.0 with 6N sulfuric acid, the bacterial cells were separated, and the bacterial cells were further washed with water, the washing solution was filtered, and the culture solution was mixed with the previously filtered culture solution. Combined. 4.31 of the superculture solution obtained in this way was added to 4N sodium hydroxide to pH 6.0.
Return to Amberlight IRC-50 (product name)
The target compound [ ] was adsorbed by passing through a column packed with 95 ml of [Na + ]. The column was thoroughly washed with water and eluted with 0.5N sulfuric acid 1.1 to obtain a solution containing the crude target compound [ ]. Add 3.0g of sodium paratoluenesulfonate to this solution and
Gradually add the specified sodium hydroxide to bring the pH to 5.0.
Adjusted to. Add this solution to Diaion CHP-20P.
(trade name) 75 ml column to adsorb the target compound. The column was filled with 200 ml of hydrochloric acid water (PH
After washing with 2.0), concentration gradient column chromatography was performed with 0 to 8% methanol water using hydrochloric and acidic water (PH2.0). Each fraction (10 each
ml) was searched for using high performance liquid chromatography and the compound [] was confirmed. By the way, the operation and conditions of high performance liquid chromatography used at this time were Deveroseal ODS-5 (C-20%, 5Ό) on the column.
[Product name] (6mmÏÃ200mm) was used, and the eluent was 0.2
A solution prepared by adding 4% acetonitrile to a 0.1% acetic acid solution containing 0.02 mol of sodium sulfate and 0.02 mol of sodium 1-pentanesulfonate as a counterion agent is fed at a rate of 1 ml per minute. In addition, ortho-phthalaldehyde reagent (hereinafter abbreviated as OPA) was used to detect this substance.
A solution of 0.6 mg/ml dissolved in 10 boric acid buffer is used. After the sample was injected, the eluent eluted from the column was reacted with the OPA solution in a mixing joint, and the target compound was detected with a UV detector at a wavelength of 344 mΌ. According to this operating method, the retention time of the target compound [] is 7 minutes 28 seconds (the first
Table). The compound [] searched in this way was fractionated into fractions 224 to 242, so these were collected and concentrated to about 40 ml, and the pH was adjusted to 6.0 using a 0.4N sodium chloride solution. This fraction of the target compound [] was passed through a 3 ml column of Amberlite IRC-50 (trade name) [Na + ] to adsorb the target compound []. After thoroughly washing with water, the mixture was eluted with 0.5N sulfuric acid and fractionated into 5ml portions. The target compound [] was assayed by the paper disk method on a plate using Bacillus subtilis PC219 as the test bacterium. Paper disks were neutralized with ammonia gas before assay. Fractions 1 to 8 can also be determined by testing positive for ninhydrin.
After confirming that it was fractionated, the fractions were collected and the pH was adjusted to 6.02 with 0.4N sodium hydroxide solution. The thus obtained fraction of the target compound [] was adsorbed on a column packed with 25 ml of activated carbon, thoroughly washed with 100 ml of water, and then eluted with 50% aqueous methanol containing 0.05N sulfuric acid. Each fraction (5 ml each) was assayed on a Bacillus subtilis PCI219 plate medium using the paper disc method. At this time, the paper disk was neutralized with ammonia gas before the assay. As a result, the target compound [] was eluted from fractions 3 to 40, so it was collected, concentrated, methanol was removed, and then neutralized using Amberlite IRA-45 (trade name) [OH - ]. After that, about 1ml
It was further concentrated to This concentrated solution was charged to a 10 ml column of Amberlite IRA-400 (trade name) [SO 4 -- ], eluted with water, and fractionated into 5 ml fractions each. Each fraction was assayed by the paper disc method using Bacillus subtilis PCI219, and after confirming that the target compound was contained in fractions 1 to 5 by testing positive for ninhydrin, the fractions were collected and 0.5 Concentrate to 18.1 ml and lyophilize to 18.1 ml.
mg of the target compound [ ] as a white powder was obtained. The physical and chemical properties of this substance, especially the measurement results of mass spectra, nuclear magnetic resonance spectra, and infrared absorption spectra, as well as Ho Chi Micin B
Based on the fact that it was derived from the formula [-1], it was identified as 1-epi-2''-formimidoylhotimicin A, ie, 1-epi-dactymicin, represented by the above formula [-1].
第ïŒå³ã¯æ¬çºæã«ããïŒâãšããã¯ããã·ã³ã®
èµ€å€ç·åžåã¹ãã¯ãã«ïŒKBré ïŒã§ããã第ïŒ
å³ã¯ïŒâãšããã¯ããã·ã³ã®æ žç£æ°å
±é³Žã¹ãã¯ã
ã«ã§ããã
Figure 1 shows the infrared absorption spectrum of 1-epidactymicin (KBr tablet) according to the present invention;
The figure is a nuclear magnetic resonance spectrum of 1-epidactymicin.
Claims (1)
å¡©ã ïŒ ããŒããã·ã³ïŒ¢ã«ãã¹ãã¬ãããã€ã»ã¹å±ã«
å±ããŠããŒããã·ã³ïŒ¢ã®ïŒäœã¢ããåºããšãåã
äžã€ïŒäœã¡ãã«ã¢ããåºã«ãã«ã ã€ããã€ã«ã°ãª
ã·ã«åºãå°å ¥ããèœåãæããèãäœçšãããã
ãšãç¹åŸŽãšãã次ã®ç«äœæ§é åŒ ã§ç€ºãããïŒâãšããã¯ããã·ã³ã®è£œé æ¹æ³ã ïŒ ããŒããã·ã³ïŒ¢ã«ã¹ãã¬ãããã€ã»ã¹ã»ãã³
ãžããªãšã³ã·ã¹ïŒStreptomyces tenjimariensisïŒ
SSâ1507 â41ïŒåŸ®å·¥ç èå¯ç¬¬7625å·ïŒãäœçš
ãããç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®æ¹æ³ã ïŒ ã¹ãã¬ãããã€ã»ã¹ã»ãã³ãžããªãšã³ã·ã¹ã
å¹é€äžã®å¹é€æ¶²å ã«ããŒããã·ã³ïŒ¢ãååšãããŠ
äœçšãããç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé ã®æ¹æ³ã[Claims] First-order three-dimensional structural formula 1-epidactymicin or an acid addition salt thereof. 2. The following, characterized in that a bacterium belonging to the genus Streptomyces and having the ability to epitomize the amino group at the 1-position of Hotimicin B and introduce a formimidoylglycyl group into the methylamino group at the 4-position is allowed to act on Hotimicin B. 3D structural formula of A method for producing 1-epidactymicin. 3 Streptomyces tenjimariensis in Hochimishin B
The method according to claim 2, in which SS-1507 U-41 (Feikoken Bibori No. 7625) is applied. 4. The method according to claim 2, wherein Hotimicin B is present in the culture medium during which Streptomyces tenzimariensis is being cultured.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11304384A JPS60258196A (en) | 1984-06-04 | 1984-06-04 | Novel dactimicin derivative and its preparation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11304384A JPS60258196A (en) | 1984-06-04 | 1984-06-04 | Novel dactimicin derivative and its preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS60258196A JPS60258196A (en) | 1985-12-20 |
JPH0463874B2 true JPH0463874B2 (en) | 1992-10-13 |
Family
ID=14602035
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP11304384A Granted JPS60258196A (en) | 1984-06-04 | 1984-06-04 | Novel dactimicin derivative and its preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS60258196A (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5743694A (en) * | 1980-08-26 | 1982-03-11 | Meiji Seika Kaisha Ltd | Preparation of antibiotic dactimicin |
-
1984
- 1984-06-04 JP JP11304384A patent/JPS60258196A/en active Granted
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5743694A (en) * | 1980-08-26 | 1982-03-11 | Meiji Seika Kaisha Ltd | Preparation of antibiotic dactimicin |
Also Published As
Publication number | Publication date |
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JPS60258196A (en) | 1985-12-20 |
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